Targeting the EGF Receptor for Ovarian Cancer Therapy

Abstract

Ovarian carcinoma is the leading cause of death from gynecologic malignancy in the US. Factors such as the molecular heterogeneity of ovarian tumors and frequent diagnosis at advanced stages hamper effective disease treatment. There is growing emphasis on the identification and development of targeted therapies to disrupt molecular pathways in cancer. The epidermal growth factor (EGF) receptor is one such protein target with potential utility in the management of ovarian cancer. This paper will discuss contributions of EGF receptor activation to ovarian cancer pathogenesis and the status of EGF receptor inhibitors and EGF receptor targeted therapies in ovarian cancer treatment.

Increased DNA methyltransferase activity and DNA methylation following epidermal growth factor stimulation in ovarian cancer cells

“…This work may have clinical significance given that the ovarian tumor environment contains numerous EGFR activators 2 and approximately 35% of all ovarian cancer tumors are positive for activated EGFR. 3,4 Using an in vitro paradigm of EGF exposure of OVCA 433 cells, we found that acute and long-term EGFR activation increases DNMT activity. It is important to note the observed increase in DNMT activity is an increase in total DNMT activity and does not distinguish the relative contributions of the maintenance methyltransferase (DNMT1) or de novo methyltransferases t-test showed a significant increase in DNMt activity in HS68 cells treated with 10 nM EGf, n = 3.…”

“…2 The presence of these activators in patient ascites suggests that the tumor microenvironment is under chronic EGFR activation and may account for the observation that approximately 35% of all ovarian cancer tumors are positive for activated EGFR (tyrosine phosphorylated EGFR). 3,4 Overexpression of EGFR, and its ligands, has been detected in ovarian tumors and correlates with poor prognosis. 3,5,6 EGFR is a member of the receptor tyrosine kinase family that possesses intrinsic tyrosine kinase activity.…”

“…3,4 Overexpression of EGFR, and its ligands, has been detected in ovarian tumors and correlates with poor prognosis. 3,5,6 EGFR is a member of the receptor tyrosine kinase family that possesses intrinsic tyrosine kinase activity. Activation of EGFR stimulates numerous downstream signaling cascades including Ras and Extracellular-signal Regulated Kinase (ERK)/Mitogen Activated Protein Kinase (MAPK), which are associated with cell growth, proliferation, survival, angiogenesis, cell migration, cell-cell/cell-matrix interaction and tumor metastasis.…”

“…Activation of EGFR stimulates numerous downstream signaling cascades including Ras and Extracellular-signal Regulated Kinase (ERK)/Mitogen Activated Protein Kinase (MAPK), which are associated with cell growth, proliferation, survival, angiogenesis, cell migration, cell-cell/cell-matrix interaction and tumor metastasis. 2,3,7,8 Activation of EGFR is also reported to induce an epithelial to mesenchymal transition (EMT). 2,3,9,10 EMT is important in ovarian cancer progression is correlated with accumulation of aberrant CpG island methylation.…”

“…2,3,7,8 Activation of EGFR is also reported to induce an epithelial to mesenchymal transition (EMT). 2,3,9,10 EMT is important in ovarian cancer progression is correlated with accumulation of aberrant CpG island methylation. in ovarian cancer, ascites fluid contains numerous epidermal growth factor receptor (EGfr) activators, which could result in a tumor microenvironment of constant EGfr activation.…”